Cancer Cell
Volume 31, Issue 2, 13 February 2017, Pages 270-285
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Article
MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

https://doi.org/10.1016/j.ccell.2016.12.005Get rights and content
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Highlights

  • MYC dramatically accelerates tumorigenesis and metastases in Rb1/Trp53 null SCLC

  • MYC promotes a NEUROD1+, neuroendocrine-low subtype with variant histopathology

  • MYC-driven SCLCs are chemo-sensitive but rapidly relapse

  • MYC sensitizes SCLC to combined Aurora kinase inhibition and chemotherapy treatment

Summary

Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low “variant” subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which, combined with chemotherapy, strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a potential targeted treatment approach for MYC-driven SCLC.

Keywords

MYC
genetically engineered mouse model
neuroendocrine
small-cell lung cancer
Aurora kinase inhibitor
chemotherapy
ASCL1
NEUROD1

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